We have developed a model system for studying how retroviruses contribute to induction of immunodeficiency. Mice infected with a mixture of murine leukemia viruses (MuLV), termed LP-BM5 MuLV, develop a syndrome characterized by early-onset lymphoproliferation and immunodeficiency and later by enhanced susceptibility to infection and development of B cell lineage lymphomas. The etiologic virus of this syndrome was found to be a replication defective MuLV with an envelope gene related to MCF MuLV. The virus is being molecularly cloned to develop further understanding of its effects on the immune system. The virus- induced disease was shown to be dependent on Ly-4+ T cells, as mice depleted in vivo of this cell subset do not develop prominent dysfunction of Ly-2+ T cells or of B cells. Analyses of lymphokines produced by Ly-4+ T cells showed that infection stimulated high-level expression of gamma interferon, but that alpha and beta interferon could not be induced. By comparison, infected mice did not produce IL-2, IL-3, IL-4, IL-6 or GM CSF. Lack of IL-2 production was associated with deficient cytotoxic T lymphocyte responses and possibly with impaired natural killer cell responses. A consequence of Ly-4+ T cell activation is the development of polyclonal B cell activation that preceeds the appearance of oligoclonal B cell proliferation and evolution of metastatic lymphomas. Development of the syndrome was found to be regulated by the major histocompatibility complex with H-2b mice being susceptible and H-2c mice resistant. This model system may prove useful for understanding the pathogenesis of HIV infections in man.